2-Decarboxy-2-hydroxymethyl-5,6-dihydro-proslacylin analogs

ABSTRACT

2-Decarboxy-2-hydroxymethyl-5,6-dihydro-prostacyclin analogs (PGI 1  derivatives) illustrated by a compound of the formula ##STR1## wherein ˜ indicates alpha or beta configuration, and the processes for producing them, said analogs having pharmacological utility.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of copending application Ser. No. 857,236 filed Dec. 5, 1977 now issued as U.S. Pat. No. 4,125,712, which was a continuation-in-part of then copending Ser. No. 788,146 filed Apr. 19, 1977, since abandoned, which was a continuation-in-part of then copending Ser. No. 691,400 filed June 1, 1976, since abandoned.

BACKGROUND OF THE INVENTION

This invention relates to products having prostacyclin-like structure and to processes for preparing them. In particular this invention relates to 2-decarboxy-2-hydroxymethyl 5,6-dihydro-prostacyclin analogs and to processes for preparing them.

The essential material for this application, including the background of the invention, the disclosure of the invention, and the description of the preferred embodiments, including Preparations and Examples, is incorporated by reference from commonly owned U.S. Pat. No. 4,125,712, under the provision of M.P.E.P. 608.01(p).

SUMMARY OF THE INVENTION

It is the purpose of this invention to provide novel products having pharmacological activity. It is a further purpose to provide processes for preparing these products and their intermediates.

The terms L, Q₂, etc. as used hereinafter are as defined in the Table of Definitions herein.

TABLE Definition of Terms for Formulas

A is

a valence bond or --(CH₂)_(h) -- where h is one, 2, or 3.

D is

(1) a valence bond; (2) --(CH₂)_(d) -- where d is one, 2, 3, 4, or 5; (3) --CH═CH--A-- where A is a valence bond or --(CH₂)_(h) -- where h is one, 2, or 3; or (4) --CH₂ --O--CH₂ --Y-- where Y is a valence bond or --(CH₂)_(k) -- where k is one or 2.

D' is

--CH₂ --CH═CH--A-- or --(CH₂)_(t) --CF₂ -- wherein A is a valence bond or --(CH₂)_(h) -- where h is one, 2, or 3; and wherein t is 2, 3, or 4.

E is

alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one to 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.

G is

nitrato, iodo, chloro, bromo, acetato, trifluoroacetato, or benzoato.

L is

(1) a valence bond, (2) --(CH₂)_(d) -- wherein d is one to 5 inclusive, (3) --(CH₂)_(t) --CF₂ -- wherein t is 2, 3, or 4, (4) --CH₂ --CH═CH--A-- wherein A is a valence bond or --(CH₂)_(h) -- wherein h is one, 2, or 3, or (5) --CH₂ --O--CH₂ --Y-- wherein Y is a valence bond or --(CH₂)_(k) -- wherein k is one or 2.

L₁ is ##STR2## or a mixture of ##STR3## wherein R₅₃ and R₅₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₅₃ and R₅₄ is fluoro only when the other is hydrogen or fluoro.

L₂ and L₃ are

hydrogen, alkyl of one to 4 carbon atoms, inclusive, or --COOR₅₁, wherein R₅₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted one, 2, or 3 chloro or alkyl of one to 3 carbon atoms, inclusive; being the same or different, with the proviso that not more than one of L₂ and L₃ is --COOR₅₁.

M is

--(CH₂)_(h) wherein h is one, 2, or 3.

M₁ is ##STR4## wherein R₅₅ is hydrogen or methyl. Q is ##STR5## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein R₄ is hydrogen, tetrahydropyran-2-yl, tetrahydrofuranyl, 1-ethoxyethyl or a group of the formula ##STR6## wherein R₈ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₉ and R₁₀ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R₉ and R₁₀ are taken together, --(CH₂)_(a) -- or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein "a" is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R₁₁ is hydrogen or phenyl.

Q₁ is ##STR7## wherein R₃ is as defined above, and wherein R₄₀ is the same as R₄ defined above except that it does not include hydrogen, but includes only the blocking groups such as tetrahydropyran-2-yl.

Q₂ is ##STR8## wherein R₃ and R₄ are as defined above for Q. Q₃ is ##STR9## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive. Q₄ is ##STR10## Q₅ is ##STR11## wherein R₄₂ is (1) tetrahydropyran-2-yl, (2) tetrahydrofuranyl, (3) 1-ethoxyethyl, (4) a group of the formula ##STR12## wherein R₈ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₉ and R₁₀ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R₉ and R₁₀ are taken together, --(CH₂)_(a) -- or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R₁₁ is hydrogen or phenyl, or (5) a silyl group of the formula --Si(E)₃ wherein E is alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.

Q₆ is ##STR13## wherein R₄₄ is R₄₂ as defined for Q₅ and hydrogen. R₁ is

hydrogen or alkyl of one to 8 carbon atoms, inclusive, or a pharmacologically acceptable cation.

R₂ is ##STR14## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro; or ##STR15## wherein R₅ and R₆ are as defined above with the proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between --CR₅ R₆ --and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different.

R₃ is

hydrogen or alkyl of one to 4 carbon atoms.

R₄ is

hydrogen, tetrahydropyran-2-yl, tetrahydrofuranyl, 1-ethoxyethyl or a group of the formula ##STR16## wherein R₈ is alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R₉ and R₁₀ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R₉ and R₁₀ are taken together, --(CH₂)_(a) -- or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein "a" is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R₁₁ is hydrogen or phenyl.

R₅ and R₆ are

hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and with the further proviso that, when Z is oxa (--O--) as defined below, neither R₅ nor R₆ is fluoro.

R₇ is

alkyl of one to 4 carbon atoms, inclusive.

R₈ is

alkyl of one to 18 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive.

R₉ and R₁₀ are

the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R₉ and R₁₀ are taken together, --(CH₂)_(a) -- or --(CH₂)_(b) --O--(CH₂)_(c) -- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4.

R₁₁ is

hydrogen or phenyl.

R₁₂ is

alkyl of one to 8 carbon atoms, inclusive.

R₁₃ is

the group --P⁺ (C₆ H₅)₃ or --P(O)(OR₁₂)₂ wherein R₁₂ is as defined above.

R₁₄ is

hydrogen or an alkali metal cation.

R₁₅ is

alkyl of one to 3 carbon atoms, inclusive.

R₁₀ is

(1) --COOR₁₇

(2) --CH₂ OH

(3) --CH₂ N(R₁₈)₂ ##STR17## wherein R₁₇ is (a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or (g) 2-naphthyl; and wherein R₁₈ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different.

R₁₇ is

as defined in R₁₆ above.

R₁₈ is

as defined in R₁₆ above.

R₁₉ is

(a) alkyl of one to 12 carbon atoms, inclusive,

(b) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(c) aralkyl of 7 to 12 carbon atoms, inclusive,

(d) phenyl,

(e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR18## wherein R₃₄ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₃₅ is hydrogen or benzoyl,

(m) hydrogen; or

(n) a pharmacologically acceptable cation R₂₀ is ##STR19## wherein R₄ is as defined above. R₂₁ is the same as R₂₀ defined above except that R₄ therein is replaced with R₄₀ as defined below, i.e. excluding hydrogen. R₂₂ is ##STR20## wherein R₄ is as defined above. R₂₅ includes

R₂, as defined above, and ##STR21## R₂₃ is R₂₆ is

a carboxyacyl blocking group: ##STR22## wherein R₂₇ is alkyl of one to 4 carbon atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, phenyl or nitro, and g is zero to 5, inclusive, provided that not more than two R₂₇ 's are other than alkyl, and that the total number of carbon atoms in the R₂₇ 's does not exceed 10 carbon atoms: ##STR23## wherein R₂₈ is alkyl of one to 4 carbon atoms, inclusive; or ##STR24## wherein R₂₇ and g are as defined above. R₂₇ is

as defined in R₂₆ above.

R₂₈ is

as defined in R₂₆ above.

R₃₀ is

(1) --COOR₁₉

(2) --CH₂ OH

(3) --CH₂ N(R₁₈)₂ ##STR25## wherein R₁₉ is (a) alkyl of one to 12 carbon atoms, inclusive,

(b) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(c) aralkyl of 7 to 12 carbon atoms, inclusive,

(d) phenyl,

(e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR26## wherein R₃₄ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₃₅ is hydrogen or benzoyl,

(m) hydrogen; or

(n) a pharmacologically acceptable cation; and wherein R₁₈ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different.

R₃₁ is

(1) --COOR₃₂

(2) --CH₂ OH, with the proviso that R₃₁ is not --CH₂ OH when D is a valence bond,

(3) --CH₂ N(R₁₈)₂, ##STR27## wherein R₃₂ is (a) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(b) aralkyl of 7 to 12 carbon atoms, inclusive,

(c) phenyl,

(d) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR28## wherein R₃₄ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, wherein R₃₅ is hydrogen or benzoyl, and

wherein R₁₈ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different; wherein ˜ indicates attachment in alpha or beta configuration; including the lower alkanoates thereof.

R₃₂ is

as defined in R₃₁ above.

R₃₃ is

iodo or bromo.

R₃₄ is

phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl.

R₃₅ is

hydrogen or benzoyl.

R₃₆ is

(1) --COOR₃₇

(2) --CH₂ OH

(3) --CH₂ N(R₁₈)₂ ##STR29## wherein R₃₇ is (a) alkyl of one to 12 carbon atoms, inclusive,

(b) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(c) aralkyl of 7 to 12 carbon atoms, inclusive,

(d) phenyl,

(e) phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, ##STR30## wherein R₃₄ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, and wherein R₃₃ is hydrogen or benzoyl, or

(m) hydrogen; and wherein R₁₈ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, benzyl, or phenyl, being the same or different.

R₃₇ is

as defined above in R₃₆.

R₃₈ is

bromo or chloro.

R₄₀ is

the same as R₄ defined above except that it does not include hydrogen, but only the blocking groups such as tetrahydropyran-2-yl. R₄₁ is ##STR31## wherein R₄₂ includes R₄₀ blocking groups as defined above, together with silyl groups of the formula-Si(E)₃ wherein E is alkyl of one to 4 carbon atoms, inclusive, phenyl, phenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.

R₄₂ is

as defined in R₄₁ . R₄₃ is ##STR32## wherein R₄₄ includes R₄₂ blocking groups and hydrogen. R₄₄ is

is as defined in R₄₃ .

R₅₁ is

hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted one, 2, or 3 chloro or alkyl of one to 3 carbon atoms, inclusive.

R₅₃ and R₅₄ are

hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₅₃ and R₅₄ is fluoro only when the other is hydrogen or fluoro.

R₅₅ is

hydrogen or methyl.

R₅₇ is

(1) --(CH₂)_(m) --CH₃ --, ##STR33## wherein m is one to 5, inclusive, T₁ is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, and s is zero, one, 2, or 3, the various T₁ 's being the same or different, with the proviso that not more than two T₁ 's are other than alkyl.

R₅₈ is

hydrogen or hydroxy.

T is

alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different.

T₁ is

chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, and s is zero, one, 2, or 3, the various T₁ 's being the same or different, with the proviso that not more than two T₁ 's are other than alkyl.

W is ##STR34## wherein R₄ is as defined above. X is

trans--CH═CH--, cis--CH═CH--, --C.tbd.C--, or --CH₂ CH₂ --.

X' is

cis--CH═CH--, --C.tbd.C--, or --CH₂ CH₂ --.

Y is

a valence bond or --(CH₂)_(k) -- where k is one or 2.

Y₁ is

trans--CH═CH--; --C.tbd.C-- or --CH₂ CH₂ --.

Z is

an oxa atom (--O--) or C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive between --CR₅ R₆ -- and the phenyl ring.

Z₁ is

(1) cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or

(2) cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --,

wherein g is one, 2, or 3.

a is

3, 4, or 5.

b is

one, 2, or 3.

c is

one, 2, or 3 with the proviso that b plus c is 2, 3, or 4.

d is

an integer of one to 5, inclusive.

g (as to (R₂₇)_(g) in carboxyacyl groups) is zero to 5, inclusive.

g (as to --(CH₂)_(g) -- in Z₁ of Preparation 1) is

one, 2, or 3.

h is

one, 2 or 3.

k is

one or 2.

m is

one to 5, inclusive.

s is

zero, one, 2, or 3.

t is

2, 3, or 4.

Hal is

chloro, bromo, or iodo.

THP is

tetrahydropyran-2-yl.

Ts is

p-toluenesulfonyl.

The symbol ˜ (wavy line) indicates

attachment in alpha or beta configuration.

C_(g) H_(2g) is

alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl.

C_(j) H_(2j) is

a valence bond or alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive between --CR₅ R₆ -- and the phenyl ring.

Merely illustrative but not limiting are compounds of the following formula: ##STR35## 

I claim:
 1. A cyclic ether of the formulawherein D is (1) a valence bond; (2) --(CH₂)_(d) -- where d is one, 2, 3, 4, or 5; (3) --CH═CH--A-- where A is a valence bond or --(CH₂)_(h) -- where h is one, 2, or 3; or (4) --CH₂ --O--CH₂ --Y-- where Y is a valence bond or --(CH₂)_(k) -- where k is one or 2; wherein R₂ is ##STR36## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro; or ##STR37## wherein R₅ and R₆ are as defined above with the proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between --CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; wherein Q₃ is ##STR38## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₂₃ is ##STR39## wherein R₃₁ is --CH₂ OH with the proviso that R₃₁ is not --CH₂ OH when D is a valence band, and wherein ˜ indicates attachment in alpha or beta configuration; including the lower alkanoates thereof.
 2. A compound according to claim 1 wherein Q₃ is ##STR40## wherein R₃ is as defined in claim
 1. 3. A compound according to claim 2 wherein R₃ is hydrogen and R₂₃ is ##STR41##
 4. A compound according to claim 3 wherein D is a valence bond or --(CH₂)_(d) -- wherein d is one, 2, 3, 4, or
 5. 5. A compound according to claim 4 wherein D is trimethylene.
 6. A compound according to claim 5 wherein R₂ is n-pentyl.
 7. A cyclic ether of the formula ##STR42## wherein D is (1) a valence bond; (2) --(CH₂)_(d) -- where d is one, 2, 3, 4, or 5; (3) --CH═CH--A-- where A is a valence bond, or --(CH₂)_(h) -- where h is one, 2, or 3; or (4) --CH₂ --O--CH₂ --Y-- where Y is a valence bond or --(CH₂)_(k) -- where k is one or 2;wherein Q₃ is ##STR43## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₂₃ is ##STR44## wherein R₃₀ is --CH₂ OH and wherein ˜ indicates attachment in alpha or beta configuration; including the lower alkanoates thereof.
 8. A compound according to claim 7 wherein Q₃ is ##STR45## wherein R₃ is as defined in claim
 29. 9. A compound according to claim 8 wherein R₂₃ is ##STR46##
 10. A compound according to claim 9 wherein D is a valence bond or --(CH₂)_(d) -- wherein d is one, 2, 3, 4, or
 5. 11. A cyclic ether of the formula ##STR47## wherein D' is --CH₂ --CH═CH--A-- or--(CH₂)_(t) --CF₂ --wherein A is a valence bond or --(CH₂)_(h) -- where h is one,
 2. or 3; and wherein t is 2, 3, or 4;wherein Q₃ is ##STR48## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₂₃ is ##STR49## wherein R₂₅ is ##STR50## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro; ##STR51## wherein R₅ and R₆ are as defined above with the proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between --CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; or ##STR52## wherein R₃₀ is --CH₂ OHand wherein ˜ indicates attachment in alpha or beta configuration; including the lower alkanoates thereof.
 12. A compound according to claim 11 wherein Q₃ is ##STR53## wherein R₃ is as defined in claim
 35. 13. A compound according to claim 12 wherein R₂₃ is ##STR54##
 14. A compound according to claim 13 wherein D' is --(CH₂)_(t) --CF₂ where t is 2, 3, or
 4. 15. A compound according to claim 13 wherein D' is --CH₂ CH═CH--A-- wherein A is a valence bond or --(CH₂)_(h) wherein h is one, 2, or
 3. 16. A cyclic ether of the formula ##STR55## wherein L is (1) a valence bond, (2) --(CH₂)_(d) -- wherein d is one to 5 inclusive, (3) --(CH₂)_(t) --CF₂ -- wherein t is 2, 3, or 4, (4) --CH₂ --CH═CH--A-- wherein A is a valence bond or --(CH₂)_(h) -- wherein h is one, 2, or 3, or (5) --CH₂ --O--CH₂ --Y-- wherein Y is a valence bond or --(CH₂)_(k) -- wherein k is one or 2; wherein Q₃ is ##STR56## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₂₃ is ##STR57## wherein R₂₅ is ##STR58## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro; ##STR59## wherein R₅ and R₆ are as defined above with the proviso that neither R₅ nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between --CR₅ R₆ -- and the phenyl ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; or ##STR60## wherein R₃₀ is --CH₂ OHwherein X' is cis--CH═CH--, --C.tbd.--, or --CH₂ CH₂ --; and wherein ˜ indicates attachment in alpha or beta configuration; including the lower alkanoates thereof.
 17. A compound according to claim 16 wherein X' is cis--CH═CH--.
 18. A compound according to claim 16 wherein X' is --C.tbd.C--.
 19. A compound according to claim 18 wherein Q₃ is ##STR61## wherein R₃ is as defined in claim
 16. 20. A compound according to claim 19 wherein R₂₃ is ##STR62##
 21. A compound according to claim 18 wherein Q₃ is ##STR63## wherein R₃ is as defined in claim
 16. 22. A compound according to claim 21 wherein R₂₃ is ##STR64##
 23. A compound according to claim 16 wherein X' is --CH₂ CH₂ --.
 24. A compound according to claim 23 wherein Q₃ is ##STR65## wherein R₃ is defined as in claim
 16. 25. A compound according to claim 24 wherein R₂₃ is ##STR66##
 26. A compound according to claim 25 wherein L is --(CH₂)_(d) -- wherein d is one to 5, inclusive.
 27. A compound according to claim 25 wherein L is --(CH₂)_(t) --CF₂ wherein t is 2, 3, or
 4. 28. A compound according to claim 25 wherein L is --CH₂ --CH═CH--A-- wherein A is a valence bond or --(CH₂)_(h) -- wherein h is one, 2, or
 3. 